Musculoskeletal diseases and injuries represent a major burden on healthcare systems worldwide, a burden that will only continue to grow as our population continues to age. In addition to the pressing healthcare issues related to musculoskeletal disease, its effects on quality of life can be devastating. This is especially true in the case of traumatic composite injuries involving bone and the surrounding soft tissue. These types of injuries, commonly seen in combat veterans, comprise one of the most challenging environments to regenerate tissue and restore normal function. Deriving from common mesodermal precursors, it is likely that skeletal muscle and bone share common signaling pathways and use these pathways to coordinate homeostasis and regeneration. Previous reports, and our own preliminary data, indicate that activin receptor signaling is a possible candidate to coordinate the mass of these two adjacent tissues, as this pathway exerts analogous regulatory functions in each tissue individually. The studies outlined in this proposal will answer fundamental questions regarding the role of activin receptor signaling in bone and muscle healing, and provide critical insight into the future development of targeted therapeutics for the treatment of traumatic injuries. We envision that it will be possible to apply local biologcs that target activin receptor signaling, such as the soluble activin receptors we have used in the parent grant and the preliminary studies above, to provide a synchronized regenerative approach to composite musculoskeletal injuries. We believe the combined and complementary expertise of our collaborative team in mouse genetics, bone and muscle biology, and regenerative medicine provides a remarkably fertile environment to investigate the physiological mechanisms of muscle-bone interaction, specifically through the activin receptor signaling pathway during healing, so that we can ultimately develop advanced therapeutics to regenerate bone and muscle in devastating traumatic injuries.